Hydantoin derivatives for treating complications of diabetes

ABSTRACT

Hydantoin derivatives and salts thereof, intermediates therefor, process for the preparation thereof, and medicines containing the derivative, wherein said derivatives have the formula ##STR1## wherein one of V and W is hydrogen and the other is a halogenomethyl group, 1H-tetrazol-5-yl radical, --COOR group, 
     in which R is hydrogen atom, an alkyl group, --(CH 2  CH 2  O)nCH 3  group (n is an integer of 1 to 113) or substituted phenyl, ##STR2##  in which R 1  and R 2  are same or different independently, each is hydrogen atom, an alkyl group, substituted phenyl or --(CH 2  CH 2  O)nCH 3  group (n has the meaning as referred to) or R 1  may form a heterocyclic ring together with R 2  and nitrogen or oxygen atom, ##STR3##  in which R 2  and R 4  are same or different independently and each is hydrogen atom or an alkyl group, 
     X is oxygen or sulfur atom, and Y and Z are same or different independently and each is hydrogen atom, a halogen atom, alkyl group, alkoxy group, alkylmercapto group, nitro radical or --NHR 5  group, in which R 5  is hydrogen atom or an acyl group. 
     The derivatives and salts thereof are useful for the treatment of complications of diabetes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to nobel hydantoin derivatives, saltsthereof, intermediates therefor and having an optical activity, aprocess for the prepartation of same, and medicines containing thederivative or salt as an effective ingredient to treat complications ofdiabetes.

The hydantoin derivatives and intermediates are shown by followingformula.

Hydantoin derivatives ##STR4## wherein one of V and W is hydrogen andthe other is a halogenomethyl group, 1H-tetrazol-5-yl radical, --COORgroup,

in which R is hydrogen atom, an alkyl group, --(CH₂ CH₂ O)nCH₃ group (nis an integer of 1 to 113) or substituted phenyl, ##STR5## in which R₁and R₂ are same or different independently, each is hydrogen atom, analkyl group, substituted phenyl or --(CH₂ CH₂ O)nCH₃ group (n has themeaning as referred to) or R₁ may form a heterocyclic ring together withR₂ and nitrogen or oxygen atom, ##STR6## in which R₃ and R₄ are same ordifferent independently and each is hydrogen atom or an alkyl group,

X is oxygen or sulfur atom, and Y and Z are same or differentindependently and each is hydrogen atom, a halogen atom, alkyl group,alkoxy group, alkylmercapto group, nitro radical or --NHR₅, in which R₅is hydrogen atom or an acyl group.

Intermediates ##STR7## wherein Y' and Z' are same or differentindependently, each is hydrogen atom, a halogen atom or alkyl group.

2. Related Arts

Racemic 3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivativeshaving the chemical formula same with that for the intermediates havebeen known [Jap. Unexamined Pat. Appln. Gazette No. 200991/1986, "J.Med. Chem." Vol. 14, No. 8, pages 758-766 (1971) and "Liebigs Ann.Chem." pages 1552-1556 (1971)].

According to the process disclosed in said Japanese official gazette,the racemic derivatives (II-a) are prepared as shown in followingreaction formla, by brominating 4-chromanone derivative (VI), treatingwith triethylamine to remove hydrogen bromide and to form a 4-chromenonederivative (VII), treating the derivative with trimethylsilylcyanide togive cyano compound, and treating with concentrated hydrochroric acid tocause hydrolysis of the cyanide. ##STR8## wherein Y' and Z' are same ordifferent independently and each is hydrogen atom, a halogen atom oralkyl group.

However, this process can not always be said as preferable one, since itrequires the expensive reagent of trimethylsilylcyanide.

According to the process described in said J. Med. Chem., the racemicderivatives (II-b) are prepared as shown in the following reactionformula, by condensationally reacting 4-chlorophenol withα-bromo-γ-butylolactone to form the compound (VIII), oxidationallyopening the ring with chromium trioxide to form the dicarboxylic acid(IX), and then treating with concentrated surfuric acid to cause a ringclosure. ##STR9##

This process has also the disadvantage of that yield of the product isnot so high of about 55 to 66%.

According to the process described in said Liebigs Ann. Chem., theracemic derivatives (II-c) are prepared as shown in the followingreaction formula, by subjecting the monophenyl ester (X) of fumaric acidto Fries rearrangement, in the presence of aluminum chloride, and thencausing a ring closure in sodium carbonate solution. ##STR10##

This process has disadvantages of that the synthetic yield of the rawmaterial and yield of the Fries rearrangement reaction are low of about30 to 52% and 16 to 50%, respectively.

Further, please note that each of the products obtained by suchconventional processes has no optical activity and thus should be madeinto an optical active one, when the product is to be employed as theraw material to synthesize the hydantoin derivatives which are useful asthe effective ingredient for medicines to prevent or cure thecomplications of diabetes.

Turning now to the diabetes, various studies have been made to seekcompounds as effective ingredient for the medicine to prevent or curethe diabetes, which medicine can be administered in oral rout. As aresult, various compounds of sulfonyl urea, mesooxalates, guanidinederivatives have been developed and various preparations containing oneof the compounds have been marketed but each of them is of a meresymptomatic treating agent to a hyperglycoplasmia due to the diabetes.It has been known that there may be caused due to the diabetes specificchronic complications such as diabetic cataracts, diabetic neuropathy,diabetic retinopathy, diabetic nephrosis and the like but there isalmost no effective agent for curing the complications and thus it maybe said that no effective therapeutic system has been established.

Therefore, hitherto, various studies have also been made for developingan effective compound for curing such intractable diseases due to thediabetes but it is the fact that there is almost no success case. As oneof the studies, there is a search on an anti- or inhibition substance tothe enzymes of aldose reductase, since the enzyme reduces in vivo ofhuman and other animals, aldoses such as glucose and galactose intocorresponding polyols such as sorbitol and lactinol and it has beenelucidated that said complications will appear when the polyols areaccumulated at crystalline lens, peripheral nerve, kidney or the like inpatients of diabetes or galactosemia ["Jap. J. Opthalmol." Vol. 20, page399 (1976), "Int. Congr. Ser. Excerpta Med." Vol. 403, page 594 (1977),and "Metabolism" Vol. 28, page 456 (1979)].

Some of the inventors for this application have studied to find thatfollowing spiro-3-heteroazolidine derivatives and salts thereof areeffective to the complications due to the diabetes (Jap. Pat. Appln. No.41234/1985 early opened on Sept. 5, 1986 in Jap. Unexamined Pat. Appln.Gazette No. 200991/1986, which corresponding to U.S. patent applicationSer. No. 835,823 and European patent application No. 86301530.1,respectively). ##STR11## wherein T is sulfur atom or hydrogensubstituted nitrogen atom, U is oxygen atom, sulfur atom or an aminoradical, one of V' and W' is hydrogen atom or an alkyl group and theother is hydrogen atom, 1H-tetrazol-5-yl radical, --COOR₆,

in which R₆ is hydrogen atom, an alkyl group, --(CH₂ CH₂ O)nCH₃ group (nis an integer of 1 to 113) or a substituted phenyl group, ##STR12## inwhich R₁ and R₂ are same or different independently, each is hydrogenatom, an alkyl group, substituted phenyl group, --(CH₂ CH₂ O)nCH₃ group(n has the meaning as referred to) or R₁ may form a heterocyclic ringtogether with R₂ and nitrogen or oxygen atom, ##STR13## in which R₃ andR₄ are same or different independently and each is hydrogen atom or analkyl group,

X is oxygen or sulfur atom, Y" and Z" are same or differentindependently and each is hydrogen atom, a halogen atom, alkyl group,alkoxy group or alkylmercapto group, but there is no case of that one ofV' and W' is hydrogen atom and the other is hydrogen atom or an alkylgroup, when T is hydrogen substituted nitrogen atom and U is oxygenatom.

SUMMARY OF THE INVENTION

A basic object of the present invention is to provide a novel inhibitionsubstance to aldose reductase to prevent an accumulation of polyols invivo to, in turn, make prevention and curing of complications of thediabetes.

A specific object of the invention is to provide novel hydantoinderivatives and salts thereof as the inhibition substance to aldosereductase.

Another specific object of the invention is to provide a process for thepreparation of the hydantoin derivatives and salts.

A still other specific object of the invention is to provide novelintermediates for preparing the hydantoin derivatives and salts, and aprocess for the preparation of the intermediates.

According to the invention, the basic and first specific objects can beattained by the hydantoin derivatives of the formula ##STR14## whereinone of V and W is hydrogen and the other is a halogenomethyl group,1H-tetrazol-5-yl radical, --COOR group,

in which R is hydrogen atom, an alkyl group, --(CH₂ CH₂ O)nCH₃ group (nis an integer of 1 to 113) or substituted phenyl, ##STR15## in which R₁and R₂ are same or different independently, each is hydrogen atom, analkyl group, substituted phenyl or --(CH₂ CH₂ O)nCH₃ group (n has themeaning as referred to) or R₁ may form a heterocyclic ring together withR₂ and nitrogen or oxygen atom, ##STR16## in which R₃ and R₄ are same ordifferent independently and each is hydrogen atom or an alkyl group,

X is oxygen or sulfur atom, and Y and Z are same or differentindependently and each is hydrogen atom, halogen atom, alkyl group,alkoxy group, alkylmercapto group, nitro radical or --NHR₅ group, in

which R₅ is hydrogen atom or an acyl group, and salts thereof.

Namely, it has been confirmed that the hydantoin derivatives shown byFormula I and the salts thereof show an inhibition of aldose reductase,which is better than that of the spiro-3-heteroazolidine derivativesdisclosed in said Japanese official gazette and that a toxicity thereofis quite low.

In the compounds of Formula I, the term "alkyl group" may bestraight-chain alkyl radicals, branched-chain alkyl radicals orcycloalkyl radicals. As examples for the straight-chain alkyl radicals,one having 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl and the like can be listed. As examples forthe branched-chain alkyl radicals, for instance isopropyl, isobutyl,s-butyl, t-butyl and the like can be listed. As examples for thecycloalkyl radicals, one having 3 or more carbon atoms, for instancecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can belisted. As examples for the halogenomethyl group, fluoromethyl,chloromethyl, bromomethyl, iodomethyl and the like can be listed. Theterm of "halogen atom" may be fluorine, chlorine, bromine or iodine. Thesymbol "n" relates to the mean polymerization degree of ethylene glycolpart of polyethylene glycol methyl ether. As exemplar values for themean polymerization degree, 4, 7, 12, 16, 42 and 113 may be listed. Assubstituents for the substituted phenyl radical, o-, m- or p-chlorine,bromine atoms, methyl, methoxy and hydroxy radicals may be listed. Asexamples of the radical, when R₁ forms the heterocyclic ring togetherwith R₂ and nitrogen atom or oxygen atom, pyrrolidinyl, morpholino,piperidino, piperazinyl and the like radicals can be listed. As examplesfor the alkoxy group and alkylmercapto group, those having astraight-chain alkyl group, for instance methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy and the like as well asmethylmercapto, ethylmercapto, n-propylmercapto, n-butylmercapto,n-pentylmercapto, n-hexylmercapto and the like can be listed, or thosehaving a branched-chain alkyl group, for instance isopropoxy, isobutoxy,s-butoxy, t-butoxy and the like as well as isopropylmercapto,isobutylmercapto, s-butylmercapto, t-butylkmercapto and the like can belisted. As examples for the acyl group, acetyl, propanoyl, butanoyl andthe like can be listed.

The salts of the hydantoin derivatives mean that acceptable inpharmacological field and with a cation of sodium, potassium, calcium,magnesium or the like.

According to the invention, the compounds of Formula I can be preparedthrough one of following routes.

Route A

A process wherein a compound of the formula ##STR17## wherein X, Y and Zhave the meanings as referred to, and W" is a halogenomethyl group,1H-tetrazol-5-yl radical, --COOR group, ##STR18## in which R, R₁ to R₅have the meanings as referred to is reacted with a metal cyanide andammonium carbonate. The reaction for this route can be shown followingformula. ##STR19## wherein W", X, Y and Z have the meanings as referredto.

Route B

A compound of the formula ##STR20## wherein X, Y and Z have the meaningsas referred to is reacted with a metal cyanide and ammonium carbonate asin said Route A to synthesize a compound of the formula ##STR21##wherein X, Y and Z have the menings as referred to and then thiscompound is lead into 2-carboxamide derivatives (I-c), 2-esterderivatives (I-d), 2-hydroxymethyl derivatives (I-e), 2-alkoxymethylderivatives (I-f), 2-halogenomethyl derivatives (I-g) and 2-aminomethylderivatives (I-h), as shown below and in accordance with manners knownper se. ##STR22## wherein R, R₁ to R₅, X, Y and Z have the meanings asreferred to.

Regarding to the compounds (I) according to the invention, it can beestimated that two kind stereoisomers (diastereomers) will be produceddue to 2- and 4-positioned asymmetric carbon atoms in thespiro[4H-1-benzopyran-4,4'-imidazolidine] ring. According to the processshown in said Route A, it has been confirmed that one of the isomers canbe predominantly formed, the isomer can be isolated by simple operationof recrystallization, and the isomer shows higher pharmaceuticalactivity in inhibition of accumuration of sorbitol, galactitol and thelike polyols. Namely, in the Route A, a forming ratio between thepredominant isomer and the other isomers is about 5:1 to 10:1 and theformer shows 10 times or more of the latter in inhibition of polyolaccumuration.

In case of the Route B, each of single diastereomers of I-c, I-d, I-e,I-f, I-g and I-h can be prepared by using single diastereomer as the rawmaterial, which is predominantly formed among the diastereomer mixtureof the compound (I-b).

In both of the Routes A and B, the predominantly formed crystal (singlediastereomer) is dl-compound which shows a relatively high activity butthe inventors have tried an optical resolution thereof to find that eachof the d- and l-compounds has the pharmaceutical activity and that theactivity of d-compound is higher than that of the dl-compound is 2 timesor more.

There are various methods to obtain optically active d- and l-compoundsamong the compounds (I), since those can be attained by subjecting thecorresponding dl-compound to the optical resolution known per se, butone of preferable methods may be shown below.

A dl-compound among the compound (I) is treated in a conventional mannerwith a resolution agent such as brucine, cinchonine, quinine andquaternary salts thereof or the like optical active alkaloid,α-phenethylamine (d- and l-compounds), 3-aminomethylpinane (d- andl-compounds) or the like to obtain respective diastereomer salts andthen the salts are separated in a conventional manner to obtain theoptical active compounds (I). The method will be explained in moredetail, as to the case of that cinchonine-methohydroxide orquinine-methohydroxide is employed as the optical resolution agent,dl-compound among the compounds (I) is dissolved in methanol, ethanol,acetone or the like organic solvent, quinine-methohydroxide solution inequivalent amount is added thereto, and then the mixture is concentratedin vacuo to obtain N-methylquinium salt of the corresponding compound,as an amorphous substance. The amorphous substance is dissolved inmethanol, ethanol, isopropanol, acetone or the like organic solvent andthe solution is left to stand to form crystals. The crystals areobtained through a filtration of the solution and subjected torecrystallization to obtain N-methylquinium salt of the d-compound. Thesalt was treated with hydrochloric acid and recrystallized from anorganic solvent in a conventional manner to obtain the desiredd-compound (I). While the mother liquor, from which the d-compound wasfiltered off, is concentrated to obtain N-methylquinium salts of thecompounds mainly containing the 1-compound and thus the salts aretreated with hydrochloric acid to obtain crystals of the compoundscontaining mainly the l-compound. The crystals are dissolved inmethanol, ethanol, acetone or the like organic solvent,cinchonine-methohydrooxide solution in equivalent amount is addedthereto, and the mixture is concentrated in vacuo to obtainN-methylcinchonium salts of the compounds containing mainly thel-compound. The salts are dissolved in methanol, ethanol, isopropanol,acetone or the like organic solvent and left to stand to obtain crystalswhich are recrystallized to obtain N-methylcinchonium salt of thel-compound. The salt is treated with hydrochloric acid andrecrystallized from an organic solvent to obtain the desired l-compound(I).

According to said method, the d-compound is firstly obtained with use ofquinine-methohydroxide as the resolution agent and then the l-compoundis obtained with use of cinchonine-methohydroxide but this method canalso be carried out by firstly obtaining the l-compound with use ofcinchonine-methohydroxide and then obtaining the d-compound with use ofquinine-methohydroxide.

The d- and l-compounds of compounds (I-c), (I-d), (I-e), (I-f), (I-g)and (I-h) can be obtained by carrying out a similar optical resolutionwith respect to the compounds (I-b) and (I-e) to obtain corresponding d-and l-compounds and then carrying out the synthesis as shown in thereaction formula for the Route B, with use of the d- or l-compound asthe raw material.

Route C

A process wherein a compound of the formula ##STR23## wherein V, W, Xand Y have the meanings as referred to, is nitrated in 8-position, ifnecessary reduced the introduced nitro radical into amino radical and ifnecessary acylated the amino radical.

The nitration can be carried out in a manner known per se, for instancewith use of strong nitric acid under temperature of -30 to roomtemperature. The reduction of nitro radical into amino radical can alsobe carried out in conventional manner with hydrogenation in the presenceof a suitable catalyst, for instance Pt, Pd, Raney nickel or the like.As the acylating agent, an acid halide, acid anhydride, active ester andthe like reactive acid derivatives may be listed.

According to the invention, the second specific object of the inventioncan be attained by the optical active3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivatives of theformula ##STR24## wherein Y' and Z' have the meaning as refered to.

The derivatives which can be employed as the raw material for preparingoptical active hydantoin derivatives (I) can be prepared by reacting acompound of the formula ##STR25## wherein Y' and Z' have the meanings asreferred to, with maleic anhydride, causing with a base a ring closureof the resulting compound of the formula ##STR26## wherein Y' and Z'have the meanings as referred to, activating the resulting compound ofthe formula ##STR27## wherein Y' and Z' have the meanings as referredto, reacting the compound with (S)-(-)-1-methylbenzylamine, subjectingthe resulting diastereomer mixture of the formula ##STR28## wherein Y'and Z' have the meanings as referred to, to a fractionalrecrystallization, and then hydrolizing the resulting (d)- and(l)-compounds of the formula ##STR29## wherein Y' and Z' have themeanings as referred to.

It may, in general, be considered for the synthesis of the compound (IV)to utilize the acylation (Friedel-Crafts reaction) of the phenolderivative of the formula ##STR30## wherein Y' and Z' have the meaningsas referred to, with maleic anhydride but no satisfactionary result canbe obtained, since undesirable acylation to the oxygen atom of thephenol derivative will preferencially occur. In order to prevent theacylation to the oxygen atom, it necessary to protect the hydroxyradical of the phenol derivative. As the protecting radical, alkylradical such as methyl radical is selected, in view of a cost andoperability therefor. The protection by methyl radical can be easily andquantitatively carried out by using dimethyl sulfate.

Therefore, in the first step, the anisole derivative (III) formed byprotecting hydroxy radical of the phenol derivative is subjected to theFriedel-Crafts acylation with maleic anhydride to form the compound(IV). The reaction conditions depend on the anisole derivative to beselected but are, in general, as follows.

It is preferable to use maleic anhydride in more than 1.1 times molaramount to the anisole derivative (III), so that the anisole derivativeis fully exhausted. As a solvent, dichloromethane, carbon tetrachloride,1,2-dichloroethane, carbon disulfide, nitrobenzene or the like may beemployed. As a catalyst, Lewis acids such as aluminum chloride, borontrifluoride, boron tribromide and the like may be listed but it ispreferable to use aluminum chloride in more than 2 times molar amount tomaleic anhydride. The reaction temperature and time depend on thesolvent selected but if dichloromethane is employed, the reaction willbe completed in 0.5 to 3 hours under reflux temperature. During thereaction, demethylation (removal of protection radical) will occur toobtain the compound (IV) (Yield: 80 to 95%).

As the base to be used in the second step for ring closing the compound(IV) to make into the racemic3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivative (II-a),sodium carbonate, potassium carbonate, sodium bicarbonate, sodiumhydroxide, potassium hydroxide or the like may be employed but sodiumbicarbonate is especially preferable among them. An amount of the baseis sufficiently 1.01 to 2.0 equivalents. As a solvent, water,water/ethanol, water/methanol or the like polar solvent may be listedbut water is most preferable. There is no groud to give a limitation onreaction temperature and the reaction smoothly proceeds at a temperatureranging from 10° to 100° C. The reaction completes by about 10 minutes,when the reaction is carried out at 100° C. The desired compound (II-a)can be obtained in relatively high yield of 90 to 95% by extracting samewith a suitable organic solvent such as ethyl acetate, after completionof the reaction.

In the third step for activating the compound (II-a) and causing thereaction with (S)-(-)-1-methylbenzylamine to make into the diastereomermixture (V-a), the activation can be carried out by converting thecompound into its acid halide, in a conventional manner. As ahalogenation agent therefor, thionyl chloride, phosphoric pentachlorideor the like can be employed in an amount of 1 to 3 equivalent one. Theactivating reaction will proceed smoothly without use any solvent but asthe solvent, benzene, dichloromethane, dichloroethane or the like may beemployed. There is no limitation on the reaction temperature and if asolvent is employed, a temperature between 10° C. and boiling point ofthe solvent may be employed. After completion of the reaction, thesolvent or excessive halogenation agent is distilled out toquantitatively obtain the activated compound (V) of acid halide, forinstance acid chloride. The reaction between this acid halide and(S)-(-)-1-methylbenzylamine can be carried out by using the reactants inequimolar amount in a suitable solvent and in the presence of a base. Asthe base for this reaction, triethylamine, pyridine and the like may belisted but triethylamine is more preferable. As the solvent,dichloromethane, dichloroethane, N,N-dimethylformamide and the like maybe listed but dichloromethane is more preferable. The reaction will, ingeneral, be completed for about 1 hour, when the reaction is carried outat a temperature between 0° and 20° C. After completion of the reaction,the reaction mixture is washed by water to obtain the diastereomermixture (V-a) with yield of 90 to 100%.

In the fourth step for fractionally recrystallizing the diastereomermixture (V-a) to convert same into the optical active compound (V),ethanol and methanol and the like alcohols may be listed as therecrystallization solvent but ethanol is preferable, which is used 5 to20 times in amount. By carrying out the recrystallization operationtwice, (d)-type compound (V) having an optical purity of more 90% e.e.can be obtained with a higher yield of 70 to 80%. While, a similarrecrystallization operation is carried out twice with use of the motherliquid to obtain (l)-type compound (V) having an optical purity of more90% e.e. and with a higher yield of 70 to 80%.

In the last of fifth step for hydrolyzing the compound (V) to convertthe same into the desired optical active compound of3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid, as the hydrolyzingagent, an acid, for instance hydrochloric acid, bromic acid, sulfuricacid or the like mineral acid may be employed but hydrochloric acid ismore preferable. As the solvent, methanol, ethanol, dioxane, acetic acidor the like may be employed but dioxane is more preferable. There is nospecific limitation on the reaction temperature and time but thereaction will be completed for about 20 hours, when it carried out at100° C. After completion of the reaction, an extraction is carried outwith use of dichloromethane or the like organic solvent to obtain thedesired compound (II) having an optical purity of more 99% e.e and witha higher yield of 85 to 95%.

The optical active hydantoin derivatives (I-b, I-c, I-d, I-e, I-f, I-gand I-h) can be synthesized by using the resulting optical activecompound (II) as the raw material. Namely, a reaction of the opticalactive compound (II), metal cyanide and ammonium carbonate gives theoptical active hydantoin compound (I-b). And, by using the resulting(d)- or (1)-type compound (I-b) as the raw material and carrying out thesynthesis in accordance with the Route B, (d)- and (l)-type compounds ofI-c, I-d, I-e, I-f, I-g and I-h can be obtained, respectively.

The d-type amido derivative (I-c) having a strong aldose reductaseinhibition can be synthesized with a higher yield by using d-typecompound (II) as raw material therefor. The d-type hydantoin derivative(I-b) derived from d-type compound (II) can be converted with a higheryield (97.1%) into d-type ester derivative (I-d). By reacting theresulting compound (I-d) with a compound of the formula ##STR31##wherein R₁ and R₂ have the meanings as referred to, in the presence orabsence of a catalyst, the d-type compound (I-c) can be obtained with ahigher yield of more than 90%. This method is quite useful forsynthesizing the compound (I-c), since the yield thereof is higher thanthat in Route B wherein the compound is synthesized through the compound(I-b). Therefore, this method is named as Route D. ##STR32##

As a solvent for amidizing reaction of the compound (I-d), methanol,ethanol, n-propanol or the like lower alcohol, tetrahydrofuran, dioxaneor the like cycroether, N,N-dimethylformamide or the like can be used.If necessary, ammonium chloride, sodium methoxide, sodium amide,butyllithium, sodium hydride or the like may be employed as a catalyst.

The reaction can be carried out at a temperature between 0° to 100° C.In case of the reaction with a lower amine, the reaction underconditions of room temperature, in methanol and in the absence ofcatalyst gives a especially preferable result.

In the manner similar to the above, l-type amido derivative (I-c) canalso be obtained with a higher yield, in accordance with this Route D,by starting from 1-type compound (II) as raw material therefor.

EFFECTS OR ADVANTAGES OF THE INVENTION

The compounds (I) and salts thereof according to the invention,especially d-type as well as dl-type compounds and more particularly thed-type compounds show an excellent inhibition to aldose reductase andthus useful as an effective ingredient for medicines for preventing orcuring complications of diabetes. Certain compounds (I) show a quite lowtoxicity (LD₅₀ =more than 5000 mg/kg), when the compound is administeredin oral route.

FORM AS MEDICINES AND DOSING AMOUNT

There is no specific limitation, when the compound or salt according tothe invention will be made into a medicine containing at least one ofthe compounds or salts, as effective ingredient. Therefore, the medicinemay be of a solid form such as tablet, pill, capsule, powder, granulesand suppository or a liquid form such as solution, suspension oremulsion, together with a conventional additive(s) and/or a carrier(s).

A dosing amount of the compound or salt for human depends on kind of thecompound or salt per se to be selected, condition of illness, age of thepatient, form of the medicine and other factors but in case for anadult, 0.1 to 500 mg/day and more particularly 1 to 150 mg/day arepreferable.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be further explained with reference toManufacturing Examples of the compounds and salts, Pharmacological TestExamples as well as Prescriptional Examples.

EXAMPLE 1dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid

A mixture of potassium cyanide (16.1 g, 0.248 mol), ammonium carbonate(71.4 g, 0.744 mol) anddl-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid 26.0 g,0.124 mol) in 237 ml of water was stirred at 65°-70° C. for 24 hours,and then at 80°-90° C. for 15 minutes. The reaction mixture was cooledto room temperature and acidified with concentrated hydrochloric acid.Resulting crystals were obtained through a filtration to give 30.6 g ofa diastereomer mixture of6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (5:1 mixture) as pale yellow crystals. The crystals wererecrystallized from water to give 20.4 g (58.8%) of the subject desiredcompound.

The compound was a single diastereomer without containing anotherdiastereomer.

Melting point: 294°-298° C. (dec.).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1770, 1750, 1720.

NMR spectrum (DMSO-d₆) δ ppm: 1.88-2.80 (2H, m), 5.23 (1H, dd),6.83-7.38 (3H, m), 8.37 (1H, br.s), 11.07 (1H, br.s).

Mass spectrum (EI/DI) m/z: 280 (M⁺), 262, 234, 219.

Elementary analysis: C₁₂ H₉ FN₂ O₅ ; Cal.: C, 51.43; H, 3.24; N, 10.00;Found: C, 51.15; H, 3.28; N, 9.98.

From the mother liquor, the other diastereomer of the subject compoundwas obtained.

In the evaluation of these diastereomers on the ability of reduction orinhibition of polyol increase in sciatic nerve of galactosemic rats, thepotency of the major diastereomer (firstly obtained one) was higher thanthat of the minor diastereomer.

EXAMPLE 2dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

(a) To a solution ofdl-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (150 g, 0.536 mol) (obtained through the process as described inExample 1) in 1.0 liter of anhydrous pyridine, silicon tetrachloride(66.6 g, 0.392 mol) was added below 10° C. After stirring the solutionfor 15 minutes at room temperature, dry ammonia gas was introduced inexcess amount below 10° C.

The mixture was stirred for 12 hours at room temperature and then pouredinto 3.0 liter of methanol. Undissolved matter was filtered off and thefiltrate was evaporated to dryness. To the residue, 1.2 liter of waterwere added. The mixture was stirred for an hour at room temperature.Resulting precipitate was obtained through a filtration andrecrystallized from methanol to give 110 g (73.2%) of the subjectdesired compound.

Melting point: 286°-300° C. (dec.).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1770, 1720, 1670.

NMR spectrum (DMSO-d₆) δ ppm: 1.83-2.67 (2H, m), 5.17 (1H, dd),6.93-7.33 (3H, m), 7.57, 7.80 (1H, br.s), 8.47 (1H, br.s), 11.07 (1H,br.s).

Mass spectrum (EI/DI) m/z: 279 (M⁺), 262, 235, 219

Elementary analysis: C₁₂ H₁₀ FN₃ O₄ ; Cal.: C, 51.62; H, 3.61; N, 15.05;Found: C, 51.79; H, 3.58; N, 14.98.

(b) To a solution of the diastereomer mixture (5:1) of6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (29.9 g, 107 mmol) (obtained through the process as described inExample 1) in 320 ml of anhydrous pyridine, silicon tetrachloride (20.7g, 122 mmol) and dry ammonia gas were added as described in said Item(a) and the similar operation was carried out to obtain crystals. Thecrystals were recrystallized from ethanol to give colorless one (14.4 g,48.5%) having physical properties same with those obtained in said Item(a).

From the mother liquor, further, another diastereomer of the subjectcompound was obtained, which has following physical properties.

Melting point: 285°-295° C. (dec.).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1765, 1724, 1660.

NMR spectrum (DMSO-d₆) δ ppm: 1.95-2.68 (2H, m), 4.55 (1H, dd),6.83-7.48 (3H, m), 7.58, 7.81 (2H, br.s), 8.98 (1H, br.s), 11.18 (1H,br.s).

Mass spectrum (EI/DI) m/z: 279 (M⁺), 236, 193, 192, 165.

Elementary analysis: C₁₂ H₁₀ FN₃ O₄ ; Cal.: C, 51.62; H, 3.61; N, 15.05;Found: C, 51.57; H, 3.62; N, 15.01.

In the evaluation of these diastereomers on the ability of reduction orinhibition of polyol increase in sciatic nerve of galactosemic rats, theactivity of the former crystals having the melting point of 286°-300° C.(dec.) was more than 10 times in comparison with that of the lattercrystals having the melting point of 285°-295° C. (dec.).

EXAMPLE 3 Optical resolution ofdl-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

(a) Preparation ofd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

To a suspension ofdl-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamidehaving the melting point of 286°-300° C. (dec.) (10.0 g, 35.8 mmol)(obtained through the process as described in Example 2) in 500 ml ofmethanol, an aqueous quinine methohydroxide solution (36.0 mmol) [J. Am.Chem. Soc., Vol. 63, page 1368 (1941)] was added dropwise under stirringin an ice bath. After stirring the mixture at room temperature for 2hours, the mixture was evaporated in vacuo to dryness. Resulting paleyellow amorphous was dissolved in 150 ml of ethanol. The solution wasconcentrated to the volume of 100 ml under reduced pressure and thenallowed to stand for 2 days.

Resulting crystals were obtained through a filtration and recrystallizedfrom ethanol to give 5.02 g of N-methyl-quiniumd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamidesalt.

Melting point: 240°-241° C. (dec.).

[α]_(D) ²⁰ : -14.3° (methanol).

Elementary analysis: C₃₃ H₃₆ FN₅ O₆ : Cal.: C, 64.17; H, 5.87; N, 11.34;Found: C, 63.82; H, 5.87; N, 11.33.

The salt (4.87 g, 7.74 mmol) was dissolved in the mixture of 17 ml ofethanol and 4.1 ml of water. To the solution under stirring in an icebath, 8.0 ml of 1N-hydrochloric acid solution were added and the mixturewas stirred at room temperature for an hour. The reaction mixture wasevaporated in vacuo to give crystalline mass, to which 97 ml of waterwere added.

After stirring the mixture at room temperature overnight, crystalsdeposited out therein were obtained through a filtration andrecrystallized from ethanol to give 1.30 g ofd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.

Melting point: 290°-291° C. (dec.).

[α]_(D) ²⁰ : +167° (methanol).

Elementary analysis: C₁₂ H₁₀ FN₃ O₄ ; Cal.: C, 51.62; H, 3.61; N, 15.05;Found: C, 51.73; H, 3.51; N, 14.99.

(b) Preparation of1-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

The mother liquor, which was the filtrate after the filtration of theprimary crystalline mass of N-methyl-quiniumd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamidesalt, was evaporated in vacuo to dryness. Resulting amorphous wasdissolved in the mixture of 40 ml of ethanol and 10 ml of water and then19 ml of 1N-hydrochloric acid solution were added dropwise to thesolution under stirring in an ice bath. After stirring at roomtemperature for an hour, the solution was evaporated in vacuo todryness. To the residue, 220 ml of water were added and the solution wasstirred at room temperature overnight.

Resulting crystals (4.88 g) deposited out therein were obtained througha filtration. To a suspension of the crystals (2.84 g) in 100 ml ofethanol under stirring in an ice bath, an aqueous cinchoninemethohydroxide solution (11.0 mmol) [J. Am. Chem. Soc., Vol. 41, page2090 (1919)] was added dropwise. After stirring at room temperature for2 hours, the solution was evaporated in vacuo to give an amorphousresidue which was dissolved in 28 ml of isopropyl alcohol, followed byallowing to stand for 2 days. Resulting crystals deposited out thereinwere obtained through a filtration and recrystallized from ethanol togive 2.49 g of N-methyl-cinchonium1-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamidesalt.

Melting point: 242°-243° C. (dec.).

[α]_(D) ²⁰ : +20.1° (methanol).

Elementary analysis: C₃₂ H₃₄ FN₅ O₅ ; Cal.: C, 65.40; H, 5.83; N, 11.92;Found: C, 65.07; H, 5.84; N, 11.82.

The salt (2.49 g, 4.23 mmol) was dissolved in the mixture of 10 ml ofethanol and 2.0 ml of water. To the solution under stirring in an icebath, 4.5 ml of 1N-hydrochloric acid solution were added dropwise andthe mixture was stirred at room temperature for an hour. The reactionmixture was evaporated in vacuo to give crystalline mass, to which 35 mlof water were added.

After stirring the mixture at room temperature overnight, crystalsdeposited out therein were obtained through a filtration andrecrystallized from ethanol to give 880 mg of1-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.

Melting point: 290°-293° C. (dec.).

[α]_(D) ²⁰ : -169° (methanol).

Elementary analysis: C₁₂ H₁₀ FN₃ O₄ ; Cal.: C, 51.62; H, 3.61; N, 15.05;Found: C, 51.69; H, 3.52; N, 14.99.

EXAMPLE 4dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid methyl ester

To a soluion ofdl-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (20.4 g, 72.9 mmol) (obtained through the process as described inExample 1) in 765 ml of methanol, 20.0 ml of concentrated sulfuric acidwere added. The mixture was refluxed for 1.5 hours and then cooled toroom temperature. Crystals deposited out therein were obtained through afiltration and dried to give 20.0 g (93.4%) of the subject desiredcompound.

Melting point: 291° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1790, 1745, 1730.

NMR spectrum (DMSO-d₆) δ ppm: 1.92-2.85 (2H, m), 3.80 (3H, s), 5.40 (1H,dd), 7.00-7.43 (3H, m), 8.43 (1H, br.s), 11.10 (1H, br.s).

Mass spectrum (EI/DI) m/z: 294 (M⁺), 262, 234, 192, 164, 137.

Elementary analysis: C₁₃ H₁₁ FN₂ O₅ ; Cal.: C, 53.06; H, 3.77; N, 9.52;Found: C, 53.07; H, 3.62; N, 9.56.

EXAMPLE 5dl-6-Fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a suspension of lithium aluminium hydride (2.30 g, 0.06 mol) in 100ml of tetrahydrofuran, a solution ofdl-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid methyl ester (11.7 g, 0.04 mol) (obtained through the process asdescribed in Example 4) in 100 ml of tetrahydrofuran was added at 5° C.After stirring the mixture for 20 hours at room temperature (15°-20°C.), the reaction mixture was poured onto 300 ml of cracked ice understirring. While cooling the solution (10°-15° C.), the solution wasacidified to pH 1 by adding concentrated hydrochloric acid and extractedwith 400 ml of ethyl acetate. The organic layer was washed with water,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo togive a solid. The solid was recrystallized from methanol to give 8.70 g(82.0%) of the subject desired compound.

Melting point: 224°-225° C. (dec.).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 3360, 1760, 1720

NMR spectrum (DMSO-d₆) δ ppm: 1.70-2.40 (2H, m), 3.50-3.86 (2H, m),4.50-4.96 (1H, m), 4.50-5.20 (1H, m), 6.80-7.47 (3H, m), 8.46 (1H,br.s), 11.00 (1H, br.s).

Mass spectrum (EI/DI) m/z: 266 (M⁺), 248, 228.

Elementary analysis: C₁₂ H₁₁ FN₂ O₄ ; Cal.: C, 54.14; H, 4.16; N, 10.52;Found: C, 53.98; H, 4.34; N, 10.35.

EXAMPLE 6 Optical resolution ofdl-6-Fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

(a) Preparation ofd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

dl-6-Fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(25.0 g, 93.9 mmol) (obtained through the process as described inExample 5) was dissolved in 2.5 liter of ethanol and to the resultingsolution, an aqueous quinine methohydroxide solution (96.1 mmol) wasadded dropwise, under cooling in an ice bath. After stirring the mixtureat room temperature for an hour, the solvent was evaporated in vacuo togive 66.0 g of the residue, which was recrystallized from methanol twiceto give 16.4 g of N-methyl-quiniumd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dionesalt.

Melting point: 235°-237° C. (dec.).

[α]_(D) ²⁰ : +5.7° (methanol).

Elementary analysis: C₃₃ H₃₇ FN₄ O₆ ; Cal.: C, 65.55; H, 6.17; N, 9.27;Found: C, 65.64; H, 6.33; N, 9.28.

The salt (16.0 g, 26.5 mmol) was added to the mixture of 610 ml of ethylacetate and 17 ml of water, and then 17 ml of 16% aqueous solution ofhydrochloric acid were added dropwise to the mixture under stirring samevigously in an ice bath. After stirring the mixture for 30 minutes, theorganic layer was separated from the aqueous layer, and the aqueouslayer was further extracted with ethyl acetate. Both of ethyl acetatelayers were combined together, dried over anhydrous sodium sulfate andevaporated in vacuo to dryness. The residue was recrystallized fromethanol to give 6.32 g ofd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione.

Melting point: 188°-189° C.

[α]_(D) ²⁰ : +222° (methanol).

Elementary analysis: C₁₂ H₁₁ FN₂ O₄ ; Cal.: C, 54.14; H, 4.16; N, 10.52;Found: C, 54.29; H, 4.25; N, 10.53.

(b) Preparation of1-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

The mother liquor, which was the filtrate after the filtration of theprimary or predominant crystalline mass of N-methyl-quiniumd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzoyran-4,4'-imidazolidine]-2',5'-dionesalt, was evaporated in vacuo to dryness. To the residue, 1.25 liter ofethyl acetate and 35 ml of water were added, and then 35 ml of 16%aqueous solution of hydrochloric acid were added dropwise to the mixtureunder stirring same vigously in an ice bath. After stirring the mixturefor 30 minutes, the organic layer was separated from the aqueous layer,and the aqueous layer was further extracted with ethyl acetate. Both ofethyl acetate layers were combined together, dried over anhydrousmagnesium sulfate and evaporated in vacuo to give 12.0 g of crystallinemass.

The crystalline mass (11.3 g, 42.4 mmol) was dissolved in 200 ml ofethanol, and an aqueous cinchonine methohydroxide solution (46.4 mmol)was added to the solution under strirring in an ice bath. After stirringthe mixture at room temperature for an hour, the solvent was evaporatedin vacuo to give the residue, which was crystallized from ethanol. Theresulting crystals were obtained through a filtration and recrystallizedfrom methanol to give 15.5 g of N-methyl-cinchonium1-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dionesalt.

Melting point: 244°-246° C. (dec.).

[α]_(D) ²⁰ : +3.8° (methanol).

Elementary analysis: C₃₃ H₃₇ FN₄ O₅ ; Cal.: C, 66.88; H, 6.14; N, 9.75;Found: C, 67.04; H, 6.32; N, 9.82.

The salt (15.0 g, 26.1 mmol) was added to the mixture of 610 ml of ethylacetate and 17 ml of water, and then 17 ml of 16% aqueous solution ofhydrochloric acid were added dropwise to the mixture under stirring samevigously in an ice bath. After stirring at room temperature the mixturefor 30 minutes, the organic layer was separated from the aqueous layer,and the aqueous layer was further extracted with ethyl acetate. Both ofethyl acetate layers were combined together, dried over anhydrous sodiumsulfate and evaporated in vacuo to dryness. The residue wasrecrystallized from ethanol to give 6.31 g of1-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione.

Melting point: 188°-189° C. (dec.).

[α]_(D) ²⁰ : -231° (methanol).

Elementary analysis: C₁₂ H₁₁ FN₂ O₄ ; Cal.: C, 54.14; H, 4.16; N, 10.52;Found: C, 54.31; H, 4.15; N, 10.54.

EXAMPLE 7dl-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a solution ofdl-6-fluoro-2,3-dihydro-2-hydroxymethylspiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(2.66 g, 10 mmol) (obtained through the process as described in Example5) in 20 ml of N,N-dimethylformamide, thionylchloride (1.19 g, 10 mmol)was added. The solution was stirred at room temperature for 2.0 hoursand further at 80°-85° C. for 4 hours. After cooling, thee reactionmixture was poured onto 100 ml of cracked ice and resulting precipitatewas obtained through a filtration. The precipitate was partitionedbetween 70 ml of ethyl acetate and 50 ml of water. The organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated invacuo to give a pale yellow solid which was chromatographed on silicagel, eluted with ethyl acetate/n-hexane (1:1) to give 2.42 g (85.1%) ofthe subject desired compound.

Melting point: 212°-214° C.

NMR spectrum 8dmsoA-d₆) δ ppm: 1.86-2.42 (2H, m), 3.90-4.30 (2H, m),4.76-5.23 (1H, m), 6.90-7.40 (3H, m), 8.46 (1H, br.s), 10.00-11.50 (1H,br.s).

Mass spectrum (EI/DI) m/z: 284 (M⁺), 248, 219, 205, 177, 164, 137.

Elementary analysis: C₁₂ H₁₀ ClFN₂ O₃ ; Cal.: C, 50.63; H, 3.54; N,9.84; Found: C, 50.77; H, 3.40; N, 9.71.

EXAMPLE 8d-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a solution ofd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(600 mg, 2.25 mmol) (obtained through the process as described inExample 6-a) in 3.00 ml of N,N-dimethylformamide, thionylchloride (0.17ml, 2.39 mmol) was added. The solution was stirred at room temperaturefor 3.0 hours and further at 80° C. for 3.0 hours. Thereafter, theoperation as described in Example 7 was carried out to give 461 mg(71.8%) of the subject desired compound.

Melting point: 239°-240° C.

[α]_(D) ²⁰ : +216° (methanol).

Elementary analysis: C₁₂ H₁₀ ClFN₂ O₃ ; Cal.: C, 50.63; H, 3.54; N,9.84; Found: C, 50.72; H, 3.49; N, 9.94.

EXAMPLE 91-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

The operation as described in Example 8 was repeated except that1-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(600 mg, 2.25 mmol) (obtained through the process as described inExample 6-b) was employed as the starting material in lieu of thecorresponding d-type compound. In this case, 492 mg (76.6%) of thesubject compound were obtained.

Melting point: 239°-240° C.

[α]_(D) ²⁰ : -217° (methanol)

Elementary analysis: C₁₂ H₁₀ ClFN₂ O₃ ; Cal.: C, 50.53; H, 3.54; N,9.84; Found: C, 50.46; H, 3.34; N, 9.86.

EXAMPLE 10dl-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a solution ofdl-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(3.6 g, 13.5 mmol) (obtained through the process as described in Example5) in 28.0 ml of N,N-dimethylformamide, thionylbromide (3.47 g, 16.7mmol) was added below 10° C. The mixture was stirred at room temperaturefor 2.0 hours and further stirred for 1.5 hours at 80° C. After cooling,the reaction mixture was poured onto 40 ml of cracked ice. Resultingaqueous solution was stirred for 30 minutes at room temperature andextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo togive a solid. The solid was recrystallized from the mixture of acetonend n-hexane to give 3.40 g (77.3%) of the subject desired compound.

Melting point: 209°-211° c.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1780, 1740, 1495.

NMR spectrum (DMSO-d₆) δ ppm: 1.87-2.43 (2H, m), 3.73-4.03 (2H, m),4.73-5.20 (1H, m), 6.83-7.47 (3H, m), 8.53 (1H, br.s), 11.05 (1H, br.s).

Elementary analysis: C₁₂ H₁₀ BrFN₂ O₃ ; Cal.: C, 43.79; H, 3.06; N,8.51; Found: C, 43.67; H, 3.02; N, 8.48.

EXAMPLE 11d-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a solution ofd-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(2.00 g, 7.51 mmol) (obtained through the process as described inExample 6-a) in 15.0 ml of N,N-dimethylformamide, thionylbromide (0.64g, 8.27 mmol) was added. The mixture was stirred at room temperature for2.0 hours and then refluxed for 1.5 hours. The reaction mixture waspoured onto 67.0 ml of cracked ice and extracted with ethyl acetate. Theorganic layer was washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The resulting residue waschromatographed on silica gel, eluted with ethyl acetate/n-hexane (1:1)to give crystals. The crystals were recrystallized from ethyl acetate togive 1.74 g (70.4%) of the subject desired compound.

Melting point: 226°-227° C.

[α]_(D) ²⁰ : +193° (methanol).

Elementary analysis: C₁₂ H₁₀ BrFN₂ O₃ ; Cal.: C, 43.79; H, 3.06; N,8.51; Found: C, 43.75; H, 2.80; N, 8.63.

EXAMPLE 121-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

The operation as described in Example 11 was repeated except that1-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(2.00 g, 7.51 mmol) (obtained through the process as described inExample 6-b) was employed as the starting material in lieu of thecorresponding d-type compound. In this case, 1.81 g (73.3%) of thesubject desired compound were obtained.

Melting point: 226°-227° C.

[α]_(D) ²⁰ : -193° (methanol).

Elementary analysis: C₁₂ H₁₀ BrFN₂ O₃ ; Cal.: C, 43.79; H, 3.06; N,8.51; Found: C, 43.50; H, 2.81; N, 8.53.

EXAMPLE 13dl-6-Fluoro-2-fluoromethyl-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To 15 ml of anhydrous tetrahydrofuran under argon atmosphere,diethylaminosulfur trifluoride (4.09 g, 25 mmol) and a solution ofdl-6-fluoro-2,3-dihydro-2-hydroxymethyl-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(3.99 g, 15 mmol) (obtained through the process as described in Example5) in 80 ml of anhydrous tetrahydrofuran were added dropwise below -50°C. The mixture was then warmed to room temperature (25° C.) and stirredfor 4.5 hours at room temperature (25°-30° C.). The solvent in themixture was evaporated in vacuo and the residue was partitioned betweenwater and ethyl acetate. The organic layer was washed with water, driedover anhydrous sodium sulfate, filtered and evaporated in vacuo todryness. The remaining residue was chromatographed on silica gel, elutedwith ethyl acetate/n-hexane (1:1) to give 1.43 g (35.6%) of the subjectdesired compound.

Melting point: 183°-185° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1780, 1730, 1495.

Mass spectrum (EI/DI) m/z: 268 (M⁺), 248, 219, 205, 197, 192, 177, 164,137.

NMR spectrum (DMSO-d₆) δ ppm: 1.83-2.43 (2H, m), 3.90-5.47 (3H, m),6.80-7.43 (3H, m), 8.50 (1H, br.s), 11.03 (1H, br.s).

REFERENCE EXAMPLEdl-2-Azidomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

A mixture ofdl-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(4.26 g, 15 mmol) (obtained through the process as described in Example7), sodium iodide (600 mg, 4 mmol) and sodium azido (1.47 g, 23 mmol) in20 ml of N,N-dimethylformamide was heated at reflux temperature for 1.5hours and then poured onto 50 ml of cracked ice. The resultingprecipitate was obtained through a filtration and then partitionedbetween ethyl acetate and water. The organic layer was washed withwater, dried over anhydrous sodium sulfate, filtered and evaporated invacuo to give a solid. The solid was chromatographed on silica gel,eluted with ethyl acetate to give 3.06 g (70.1%) of the subject desiredcompound.

Mass spectrum (EI/DI) m/z: (M⁺), 248, 192.

NMR spectrum (DMSO-d₆) δ ppm: 2.00-2.40 (2H, m), 3.56-3.93 (2H, m),4.83-5.26 (1H, m), 6.86-7.50 (3H, m) 8.48 (1H, br.s), 11.07 (1H, br.s).

EXAMPLE 14dl-2-aminomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

To a suspension of 20% Pd-C (0.6 g) in 20 ml of 50% aqueous ethanol, asolution ofdl-2-azidomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(3.0 g, 10 mmol) (obtained through the process as described in theReference Example) in 160 ml of ethanol was added at room temperature.The mixture was hydrogenated for 16 hours at room temperature underatmospheric pressure. After filtration, the filtrate was evaporated invacuo to give a solid. The solid was recrystallized from ethanol to give2.5 g (84.0%) of the subject desired compound.

Melting point: 231°-233° C. (dec.).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1775, 1725.

Mass spectrum (EI/DI) m/z: 265 (M⁺), 248.

NMR spectrum (DMSO-d₆) δ ppm: 1.67-2.67 (2H, m), 2.80 (2H, d), 4.33-5.00(1H, m), 4.83-6.00 (1H, br), 6.77-7.43 (3H, m).

EXAMPLE 15d-6-Fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(2.00 g, 7.17 mmol) (obtained through the process as described inExample 3-a) was added to 10 ml of fuming nitric acid (specific gravity:1.52) under stirring below -30° C. The reaction mixture was stirredbelow -15° C. for 40 minutes and poured onto 30 ml of cracked ice.Resulting crystals deposited out therein were obtained through afiltration and washed with water. The filtrate was further extractedwith ethyl acetate and the organic layer was evaporated in vacuo to givean additional amount of crystals.

The crystals were combined together and recrystallized from methanol togive 2.02 g (87.1%) of the subject desired compound.

Melting point: 269°-270° C.

[α]_(D) ²⁰ : +274° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1780, 1730, 1670, 1535, 1235.

Mass spectrum (EI/DI) m/z: 324 (M⁺), 237.

NMR spectrum (DMSO-d₆) δ ppm: 1.92-2.90 (2H, m), 5.10-5.50 (1H, m),7.40-8.25 (4H, m), 8.60 (1H, br), 11.25 (1H, br).

Elementary analysis: C₁₂ H₉ FN₄ O₆ ; Cal.: C, 44.45; H, 2.80; N, 17.28;Found: C, 44.54; H, 2.68; N, 17.17.

EXAMPLE 16d-8-Amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

To a solution ofd-6-fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(1.40 g, 4.32 mmol) (obtained through the process as described inExample 15) in 40 ml of methanol, platinum (IV) oxide (140 mg) was addedand the mixture was hydrogenated for 20 hours at room temperature underatmospheric pressure.

The catalyst was filtered off and the filtrate was evaporated in vacuoand the residue was recrystallized from the mixture of methanol andwater to give 1.15 g (90.6%) of the subject desired compound.

Melting point: 240°-245° C.

[α]_(D) ²⁰ : +154° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1770, 1735, 1680, 1495.

Mass spectrum (EI/DI) m/z: 294 (M⁺).

NMR spectrum (DMSO-d₆) δ ppm: 1.67-2.80 (2H, m), 4.80-5.17 (1H, m), 5.70(2H, br), 6.07 (1H, dd), 6.45 (1H, dd), 7.53 (1H, br), 7.95 (1H, br),8.28 (1H, br), 10.98 (1H, br).

EXAMPLE 17dl-6-Fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(2.00 g, 7.17 mmol) (obtained through the process as described inExample 2) was added to 6 ml of fuming nitric acid (specific gravity:1.52) under stirring at -30° C. the reaction mixture was stirred below-15° C. for an hour and poured onto 30 ml of cracked ice. Resultingcrystals deposited out therein were obtained through a filtration andwashed with water, dried and recrystallized from the mixture ofN,N-dimethylformamide and methanol to give 1.98 g (85.3%) of the subjectdesired compound.

Melting point: above 300° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1780, 1735, 1690, 1530, 1240.

Mass spectrum (EI/DI) m/z: 324 (M⁺), 237.

NMR spectrum (DMSO-d₆) δ ppm: 1.92-2.90 (2H, m), 5.10-5.50 (1H, m),7.40-8.25 (4H, m), 8.60 (1H, br), 11.25 (1H, br).

EXAMPLE 18dl-8-Amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

To a solution ofdl-6-fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(1.40 g, 4.32 mmol) (obtained through the process as described inExample 17) in 20 ml of N,N-dimethylformamide and 40 ml of methanol,platinum (IV) oxide (140 mg) was added and the mixture was hydrogenatedfor 20 hours at room temperature under atmospheric pressure.

The catalyst was filtered off and the filtrate was evaporated in vacuoand the residue was recrystallized from the mixture ofN,N-dimethylformamide and methanol to give 1.17 g (92.1%) of the subjectdesired compound.

Melting point: 295°-above 301° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1770, 1725, 1675, 1495.

Mass spectrum (EI/DI) m/z: 294 (M⁺).

NMR spectrum (DMSO-d₆) δ ppm: 1.67-2.80 (2H, m), 4.80-5.17 (1H, m), 5.70(2H, br), 6.07 (1H, dd), 6.45 (1H, dd), 7.53 (1H, br), 7.95 (1H, br),8.28 (1H, br), 10.98 (1H, br).

EXAMPLE 19dl-2-Chloromethyl-6-fluoro-2,3-dihydro-8-nitro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

dl-2-Chrolomlethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(2.00 g, 7.4 mmol) (obtained through the process as described in Example7) was added to 6 ml of fuming nitric acid (specific gravity: 1.52)under stirring at -30° C. The reaction mixture was stirred below -15° C.for 1.5 hours and poured onto 30 ml of cracked ice. Resulting crystalsdeposited out therein were obtained through a filtration, washed withwater, dried and recrystallized from methanol to give 1.81 g (78.0%) ofthe subject desired compound.

Melting point: 210°-213° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1775, 1730, 1540, 1240.

Mass spectrum (EI/DI) m/z: 329 (M⁺), 293

NMR spectrum (DMSO-d₆) δ ppm: 1.95-2.83 (2H, m), 3.90-4.10 (2H, m),4.90-5.40 (1H, m), 7.58 (1H, dd), 7.97 (1H, dd), 8.57 (1H, br), 11.23(1H, br).

EXAMPLE 20dl-8-Amino-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione

Toa solution ofdl-2-chloromethyl-6-fluoro-2,3-dihydro-8-nitro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(1.40 g, 4.26 mmol) (obtained through the process as described inExample 19) in 40 ml of methanol, platinum (IV) oxide (140 mg) was addedand the mixture was hydrogenated for 20 hours at room temperature underatmospheric pressure.

After 20 ml opf N,N-dimethylformamide was added to the mixture, thecatalyst was filtered off and the filtrate was evaporated in vacuo todryness. The residue was recrystallized from the mixture ofN,N-dimethylformamide and methanol to give 1.09 g (85.8%) of the subjectdesired compound.

Melting point: 260° C.

IR spectrum (ν_(max) ^(KRr)) cm⁻¹ : 3420, 3330, 1775, 1710, 1495.

Mass spectrum (EI/DI) m/z: 299 (M⁺).

NMR spectrum (DMSO-d₆) δ ppm: 1.80-2.65 (2H, m), 3.78-4.10 (2H, m),4.65-5.35 (3H, m), 6.08 (1H, dd), 6.45 (1H, dd), 8.40 (1H, br), 10.93(1H, br).

EXAMPLE 21d-8-Acetamido-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

To a solution ofd-8-amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(700 mg, 2.38 mmol) (obtained through the process as described inExample 16) in 15 ml of pyridine, acetyl chloride (190 mg, 2.42 mmol)was added.

The reaction mixture was stirred at room temperature for 4 hours andthen evaporated in vacuo to dryness. The residue was chromatographed onsilica gel, eluted with chloroform/methanol (5:1) to give crystals. Thecrystals were crystallized from methanol to give 615 mg (76.9%) of thesubject desired compound.

Melting point: 202°-203° C.

[α]_(D) ²⁰ : +136° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1780, 1725, 1675, 1540, 1450.

Mass spectrum (EI/DI) m/z: 336 (M⁺), 277.

NMR spectrum (DMSO-d₆) δ ppm: 1.70-2.80 (2H, m), 2.20 (3H, s), 4.93-5.35(1H, m), 6.78 (1H, dd), 7.73 (1H, br), 7.96 (1H, dd), 8.20 (1H, br),8.43 (1H, br), 9.55 (1H, br), 11.10 (1H, br).

EXAMPLE 22 (E)-4-(5-Fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid

Into 100 ml of 1,2-dichloroethane, maleic anhydride (11.3 g, 114 mmol)and anhydrous aluminum chloride (31.0 g, 228 mmol) were dissolved byheating at 50° C. for 15 minutes, and then p-fluoroanisole (12.6 g, 100mmol) was added dropwise. The mixture was refluxed for an hour and thenpoured into 60 ml of concentrated hydrochloric acid with 400 g ofcracked ice. Resulting crystals deposited out therein were obtainedthrough a filtration, washed with water and dried in vacuo to give 16.0g (80.0%) of the subject desired compound as yellow crystals.

Melting point: 189°-191° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1733, 1648.

NMR spectrum (DMSO-d₆) δ ppm:

6.70 (1H, d, J=16.0 Hz), 6.7-8.0 (3H, m), 8.00 (1H, d, J=16.0 Hz).

EXAMPLE 23 6-Fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid

Sodium bicarbonate (2.10 g, 25.0 mmol) was added to a suspension of(E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (5.00 g, 23.8mmol) (obtained through the process as described in Example 22) in 200ml of distilled water and the mixture was refluxed for 10 minutes. Aftercooling, the reaction mixture was acidified to pH 1.0 with concentratedhydrochloric acid and then extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate and evaporated in vacuo togive crude crystals which were recrystallized from the mixture of waterand methanol to give 4.60 g (92.1%) of the subject desired compound ascolorless crystals.

Melting point: 163°-164° C.

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 1755, 1650.

Mass spectrum (EI/DI) m/z: 210 (M⁺), 165.

NMR spectrum (DMSO-d₆) δ ppm: 3.08 (1H, d, J=8.0 Hz), 3.10 (1H, d, J=6.0Hz), 5.33 (1H, dd, J=8.0 and 6.0 Hz), 7.1-7.8 (3H, m).

EXAMPLE 24 d- and1-N-[(S)-1-Methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide

Thionylchloride (71.5 g, 0.600 mol) was added to the solution ofdl-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (84.0 g,0.400 mol) (obtained through the process as described in Example 23) in840 ml of 1,2-dichloroethane. After refluxed for an hour, the reactionmixture was evaporated in vacuo to give crystals (91.0 g) of6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carbonyl chloride. Thecrystals were dissolved in 50 ml of dichloromethane and resultingsolution was added dropwise at 0° to 5° C. into a solution of(S)-(-)-1-methylbenzylamine (48.4 g, 0.400 mol) and triethylamine (40.5g, 0.400 mol) in 800 ml of dichloromethane.

The mixture was stirred for an hour and then partitioned with water.Dichloromethane layer was separated, dried over anhydrous sodium sulfateand evaporated in vacuo to give crystals (124 g, 99.0%) of diastereomermixture ofN-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide.

The diostereomer mixture was recrystallized from 1 liter of ethanoltwice to give 41.8 g (67.5%) ofd-N-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide.

Melting point: 170°-172° C.

[α]_(D) ²⁰ : +5° (methanol).

Mass spectrum (EI/DI) m/z: 313 (M⁺), 105.

NMR spectrum (CDCl₃) δ ppm: 1.48 (3H, d, J=7.0 Hz), 2.7-3.4 (2H, m),4.8-5.5 (2H, m), 6.8-7.7 (9H, m).

The mother liquor, which was the filtrate after the filtration of thecrystalline mass ofd-N-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide,was evaporated in vacuo to dryness. The residue was recrystallized from1 liter of the mixture of ethyl acetate and n-hexane (2:1) twice to give24.4 g (39.4%) of1-N-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide.

Melting point: 127°-128° C.

[α]_(D) ²⁰ : -108° (methanol).

Mass spectrum (EI/DI) m/z: 313 (M⁺), 105

NMR spectrum (CDCl₃) δ ppm: 1.53 (3H, d, J=7.0 Hz), 2.7-3.4 (2H, m),4.8-5.5 (2H, m), 6.8-7.7 (9H, m).

EXAMPLE 25 d-6-Fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylicacid

A mixture ofd-N-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide(127 g, 0.410 mol) (obtained through the process as described in Example24), concentrated hydrochloric acid (600 ml) and 1,4-dioxane (800 ml)was refluxed for 2 hours. After cooling, the reaction mixture wasextracted twice with dichloromethane.

The organic layer was dried over anhydrous sodium sulfate and evaporatedin vacuo to give 72.9 g (85.5%) of the subject desired compound ascolorless crystals.

Melting point: 175°-177° C.

[α]_(D) ²⁰ : +58° (methanol).

Mass spectrum (EI/DI) m/z: 210 (M⁺), 165.

H-NMR spectrum (DMSO-d₆) δ ppm: 3.08 (1H, d, J=8.0 Hz), 3.10 (1H, d,J=6.0 Hz), 5.33 (1H, dd, J=8.0 and 6.0 Hz), 7.1-7.8 (3H, m).

Elementary analysis: C₁₀ H₇ FO₄ ; Cal.: C, 57.15; H, 3.36; Found: C,57.10; H, 3.29.

EXAMPLE 26 1-6-Fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylicacid

The operation as described in Example 25 was repeated except that1-N-[(S)-1-methylbenzyl]-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxamide(110 g, 0.350 mol) (obtained through the process as described in Example24) was employed as the starting material in lieu of the correspondingd-type compound. In this case, 68.2 g (92.4%) of the subject desiredcompound were obtained.

Melting point: 173°-175° C.

[α]_(D) ²⁰ : -56° (methanol).

Mass spectrum (EI/DI) m/z: 210 (M⁺), 165.

H-NMR spectrum (DMSO-d₆) δ ppm: 3.08 (1H, d, J=8.0 Hz), 3.10 (1H, d,J=6.0 Hz), 5.33 (1H, dd, J=8.0 and 6.0 Hz), 7.1-7.8 (3H, m).

EXAMPLE 27d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid

The operation as described in Example 1 was repeated except thatd-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (54.8 g,0.216 mol) (obtained through the process as described in Example 25) wasemployed as the starting material in lieu of the corresponding dl-typecompound. In this case, 35.5 g (48.6%) of the subject desired compoundwere obtained.

Melting point: 146° C.

[α]_(D) ²⁷ : +194° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 3336, 1787, 1735, 1718.

Mass spectrum (EI/DI) m/z: 280 (M⁺), 262, 164.

EXAMPLE 281-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid

The operation as described in Example 1 was repeated except that1-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (250 g,1.19 mol) (obtained through the process as described in Example 26) wasemployed as the starting material in lieu of the corresponding dl-typecompound. In this case, 202 g (48.6%) of the subject desired compoundwere obtained.

Melting point: 145° C.

[α]_(D) ²⁷ : -193° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 3338, 1787, 1735, 1716.

Mass spectrum (EI/DI) m/z: 280 (M⁺), 262, 164.

EXAMPLE 29d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid n-propyl ester

A mixture ofd-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (5.0 g, 0.018 mol) (obtained through the process as described inExample 27), concentrated sulfuric acid (0.125 ml, 2.35 mmol), benzene(5 ml, 0.056 mol) and n-propyl alcohol (20 ml, 0.268 mol) was refluxedfor 5.0 hours, while azeotropically removing water by setting aDean-Stark trap. The reaction mixture was concentrated to half volumeand partitioned between 100 ml of ethyl acetate and 50 ml of 5% aqueoussolution of sodium bicarbonate. The organic layer was separated from theaqueous layer, dried over anhydrous sodium sulfate and evaporated invacuo to dryness. To the residue, 50 ml of water were added and then theaqueous solution was stirred for an hour. Resulting crystals depositedout therein were obtained through a filtration and dried to give 5.60 g(97.1%) of the subject desired compound.

Melting point: 197°-200° C.

[α]_(D) ²⁶ : +165° (methanol).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 3340, 3265, 1788, 1750, 1720.

Mass spectrum (EI/DI) m/z: 322 (M⁺), 192.

Elementary analysis: C₁₅ H₁₅ FN₂ O₅ ; Cal.: C, 55.90; H, 4.69; N, 8.69;Found: C, 55.91; H, 4.66; N, 8.88.

EXAMPLE 301-6-Fluoro-2,3-dihyro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid n-propyl ester

The operation as described in Example 29 was repeated except that1-6-fluoro-3,4-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (5.0 g, 18 mmol) (obtained through the process as described inExample 28) was employed as the starting material in lieu of thecorresponding d-type compound. In this case, 5.7 g (quantitative) of thesubject desired compound were obtained.

[α]_(D) ²⁶ : -163° (methanol).

Elementary analysis: C₁₅ H₁₅ FN₂ O₅ ; Cal.: C, 55.90; H, 4.69; N, 8.69;Found: C, 55.98; H, 4.79; N, 8.67.

EXAMPLE 31dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid n-propyl ester

The operation as described in Example 29 was repeated except thatdl-6-fluoro-3,4-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (5.0 g, 18 mmol) (obtained through the process as described inExample 1) was employed as the starting material in lie of thecorresponding d-body compound. In this case, 5.7 g (quantitative) of thesubject desired compound were obtained.

Melting point:

Mass spectrum (EI/DI) m/z: 322 (M⁺), 192.

NMR spectrum (DMSO-d₆) δ ppm: 0.92 (3H, t), 1.68 (2H, hexlet), 2.00-2.90(2H, m), 4.20 (2H, t), 5.38 (1H, dd), 6.90-7.50 (3H, m), 8.48 (1H,br.s), 11.10 (1H, br.s).

Elementary analysis: C₁₅ H₁₅ FN₂ O₅ ; Cal.: C, 55.90; H, 4.69; N, 8.69;Found: C, 55.93; H, 4.65; N, 8.87.

EXAMPLE 32d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid methyl ester

The operation as described in Example 4 was repeated except thatd-6-fluoro-3,4-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid (35.0 g, 0.125 mol) (obtained through the process as described inExample 27) was employed as the starting material in lieu of thecorresponding dl-type compound. In this case, 33.6 g (91.6%) of thesubject desired compound were obtained.

Melting point: 340° C.

[α]_(D) ²⁰ : +186° (N,N-dimethylformamide).

IR spectrum (ν_(max) ^(KBr)) cm⁻¹ : 3350, 3280, 1790, 1740.

Mass spectrum (EI/DI) m/z: 294 (M⁺), 262.

NMR spectrum (DMSO-d₆) δ ppm: 1.92-2.85 (2H, m), 3.81 (3H, s), 5.40 (1H,dd), 6.90-7.40 (3H, m), 8.50 (1H, br), 11.12 (1H, br).

EXAMPLE 33d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

(a) To a suspension ofd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid n-propyl ester (1.00 g, 3.11 mmol) (obtained through the process asdescribed in Example 29) in 5.0 ml of methanol, an excess amount of dryammonia gas was perfused below 24° C. The mixture was stirred for 4.0hours at 20°-24° C. and then evaporated in vacuo to dryness. To theresidue, 10 ml of water were added. After stirring for an hour, theaqueous solution was acidified with 6N-hydrochloric acid solution.Resulting crystals were obtained through a filtration and dried to give800 mg (90%) of the subject desired compound which had same physicalproperties with those of the crystals obtained in Example 3-a.

(b) The operation as described in said Item a was repeated except thatd-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid methyl ester (30.0 g, 0.102 mol) (obtained through the process asdescribed in Example 32) was emploed as the starting material in lieu ofthe n-propyl ester. In this case, 20.7 g (72.6%) of the subject desiredcompound were obtained as crystals which had same physical propertieswith those of the crystals obtained in Example 3-a.

EXAMPLE 341-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide

The operation as described in Example 33-a was repeated except that1-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylicacid n-propyl ester (5.75 g, 18 mmol) (obtained through the process asdescribed in Example 30) was employed as the starting material in lieuof the corresponding d-type compound. In this case, 4.9 g (quantitative)of the subject desired compound were obtained [as crystals which hadsame physical properties with those of the crystals obtained in Example3-b].

The invention will now be further explained with reference toPharmacological Test Examples, and please note that Test Compounds andControl Compounds referred to in such Examples are as follows.

Test Compounds

A:dl-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 2),

B:d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Examples 3-a and 33)

C:1-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Examples 3-b and 34),

D:dl-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 7),

E:d-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 8),

F:1-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 9),

G:dl-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 10),

H:d-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 11),

I:1-2-Bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 12),

J:d-6-Fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 15),

K:d-8-Amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 16),

L:dl-6-Fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 17),

M:dl-8-Amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 18),

N:dl-2-Chloromethyl-6-fluoro-2,3-dihydro-8-nitro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 19),

O:dl-8-Amino-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione(Example 20),

P:d-8-Acetamido-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide(Example 21).

Control Compounds

Q:dl-6-Fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione,

R:d-6-Fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione,

S:1-6-Fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione.

Pharmacological Test Example 1

The compounds according to the invention were tested for their abilityto reduce or inhibit aldose reductase enzyme activity, in accordancewith the method of Kador and Sharpless as described in "BiophysicalChemistry" Vol. 8, page 81 (1978) and using water soluble extracts ofrat lenses. Results are given in following Tables 1 and 2 in terms ofpercent inhibition of enzyme activity with respect to the variousconcentrations of 10-10M. The selected control compounds are typical onedisclosed in Japanese Unexamined patent application Gazette No.53653/1978 introduced in the preamble of this specification. IC₅₀represents the concentration of inhibitor which gives 50% inhibition.

Pharmacological Test Example 2

The compounds according to the invention were tested for their abilityto reduce or inhibit polyol increase in the sciatic nerve ofgalactosemic rats. Rats were fed 30% galactose diet and wereadministered the compounds at the various doses of 0.4-50 mg/kg once aday for eight days. One day after the final administration (on 9th day),sciatic nerves were removed for galactitol determination. Results aregiven in following Tables 3 and 4 in terms of ED₅₀ which represents 50%effective dose. The selected control compounds are typical one describedin the aforesaid Japanese unexamined patent application Gazette.

                                      TABLE 1                                     __________________________________________________________________________              Inhibition (%)                                                      Compound  10.sup.-8 M                                                                        3.3 × 10.sup.-8 M                                                              10.sup.-7 M                                                                        3.3 × 10.sup.-7 M                                                              10.sup.-6 M                                                                        3.3 × 10.sup.-6                                                                10.sup.-5                                                                          IC.sub.50                  __________________________________________________________________________                                                       (M)                        Testing compound                                                              A         21   51     80   93     --   --     --   3.2 × 10.sup.-8      B         39   80     93   --     --   --     --   1.4 × 10.sup.-8      C         --   --     --   --     --   --     27   --                         D         --   28     53   78     --   --     --   9.0 × 10.sup.-8      E         21   38     66   --     --   --     --   4.7 × 10.sup.-8      F         --   --     --   --     28   52     74   2.9 × 10.sup.-6      G         --   22     42   70     --   --     --   1.3 × 10.sup.-7      H         --   35     59   82     --   --     --   6.8 × 10.sup.-8      I         --   --     --   --     31   54     75   2.7 × 10.sup.-6      Control compound                                                              Q         --   10     17   46     71   85     --   3.9 × 10.sup.-7      R         --   15     34   61     80   88     --   2.0 × 10.sup.-7      S         --   --     --   --     --   --     32   --                         __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________              Inhibition (%)                                                      Compound  10.sup.-8 M                                                                        2.0 × 10.sup.-8 M                                                              3.3 × 10.sup.-8 M                                                              10.sup.-7 M                                                                        3.3 × 10.sup.-7                                                                10.sup.-6 M                                                                        IC.sub.50                       __________________________________________________________________________                                                  (M)                             Testing compound                                                              J         35   69     82     --   --     --   1.4 × 10.sup.-8           K         27   --     60     70   --     --   2.5 × 10.sup.-8           L         15   --     50     88   --     --   3.1 × 10.sup.-8           M         13   --     40     74   --     --   4.4 × 10.sup.-8           N         --   --     30     59   81     --   7.6 × 10.sup.-8           O         --   --     --     38   68     85   1.7 × 10.sup.-7           P         30   56     69     --   --     --   1.8 × 10.sup.-8           Control compound                                                              R         --   --     24     29   59     76   2.6 × 10.sup.-7           __________________________________________________________________________

                  TABLE 3                                                         ______________________________________                                        Compound        ED.sub.50 (mg/kg)                                             ______________________________________                                        Testing compound                                                              A               3.3                                                           B               1.3                                                           Control compound                                                              Q               36.6                                                          R               18.0                                                          ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Compound        ED.sub.50 (mg/kg)                                             ______________________________________                                        Testing compound                                                              D               1.3                                                           E               0.6                                                           G               7.2                                                           H               2.2                                                           Control compound                                                              Q               31.5                                                          ______________________________________                                    

As apparently seen from the results given in the Tables, the compoundsaccording to the invention give fairly high reduction or inhibition ofaldose reductase. Moreover, d and dl-type products according to theinvention show superior effect and more particularly d-type productshows extremely high effect on reduction or inhibition of aldosereductase.

Pharmaceutical Agent Preparation Example 1 (Tablets)

Tablets for oral administration, each contains 50 mg of an activeingredient were prepared with following prescription and a method knownper se.

    ______________________________________                                        d-6-Fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H--1-                               benzopyran-4,4'-imidazolidine]-2-carboxamide                                  (Product of Example 3-a)  50     (g)                                          Sodium citrate            25                                                  Alginic acid              10                                                  Polyvinylpyyrolidone      10                                                  Magnesium stearate        5                                                   ______________________________________                                    

Tablets, each of which contains the active ingredient of 1.0, 4.0, 5.0,10, 25 and 100 mg, were prepared by varying the mixing amount thereof.

Pharmaceutical Agent Preparation Example 2 (Capsules)

Capsules for oral administration, each contains 10 mg of an activeingredient were prepared with following prescription and a method knownper se.

    ______________________________________                                        d-2-Chloromethyl-6-fluoro-2,3-dihydro-spiro[4H--1-                            benzopyran-4,4'-imidazolidine]-2',5'-dione                                    (Product of Example 8)    10      (g)                                         Lactose                   70                                                  Corn starch               20                                                  ______________________________________                                    

What is claimed is:
 1. A hydantoin compound of the formula ##STR33##wherein one of V and W is a hydrogen atom and the other ishalogenomethyl or CONH₂ ; Y is a halogen atom; and Z is NO₂, NH₂ or NHR,in which R is a carboxylic acyl group having 2 to 4 carbon atoms;or anon-toxic salt thereof.
 2. A compound as claimed in claim 1, which isd-6-fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.3. A compound as claimed in claim 1, which isd-8-amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.4. A compound as claimed in claim 1, which isdl-6-fluoro-2,3-dihydro-8-nitro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.5. A compound as claimed in claim 1, which isdl-8-amino-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.6. A compound as claimed in claim 1, which isdl-2-chloromethyl-6-fluoro-2,3-dihydro-8-nitro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione.7. A compound as claimed in claim 1, which isdl-8-amino-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione.8. A compound as claimed in claim 1, which isd-8-acetamido-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide.9. A composition for treating complications of diabetes, which comprisesan effective amount of at least one compound of claim 1 and apharmaceutical carrier or excipient therefor.